Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive motor neuron disease that is the leading inherited cause of infant mortality. SMA is caused by deficiency of the survival motor neuron (SMN) protein. Our long term research goal is to understand the underlying pathogenesis of SMA in order to develop effective treatment strategies for this disease. Recent studies suggest that SMA begins because of intrinsic abnormalities of both muscle and motor nerve terminals; however the nature of these defects remains unknown. Histone deacetylase (HDAC) inhibitors have been shown to increase survival of SMA mice; but it is unclear how these drugs improve muscle and/or motor neuron function. In preliminary studies in SMA mice, we have shown that at a time when the mouse is profoundly weak, there is little structural denervation. However there are widespread immature and hypotrophic myofibers as well as simplified neuromuscular junctions (NMJs). Mice treated with a pan- HDAC inhibitor show a substantial extension of survival, increase in motor function, and improvement in the size and maturity of myofibers, without a change in motor neuron number. Based on these preliminary data, we hypothesize that SMN deficiency causes an arrest of muscle maturation and/or a failure of NMJ transmission that can be overcome with HDAC inhibitors, which accelerate the development of the SMA motor unit. We further hypothesize that HDAC isoform-specific drugs will have distinct biological effects on the SMA motor unit that will provide crucial insights into the therapeutic mechanism of these compounds. We will test these hypotheses by: 1) establishing whether or not a defect of muscle development contributes to SMA by studying cultured SMA muscle cells and by rescuing SMN expression specifically in muscle tissue in conditional SMA mice, 2) determining whether or not weakness in SMA is due to an impairment of neuromuscular transmission by examining the electrophysiology and morphology of the NMJs in SMA mice, and 3) characterizing the ability of HDAC inhibitors to facilitate muscle and NMJ maturation and ameliorate SMA in mice by treating SMA muscle cells and SMA mice with broadly active and HDAC-isoform specific HDAC inhibitors. PUBLIC HEALTH RELEVANCE: This work is important for public health because spinal muscular atrophy is the leading inherited cause of infant mortality and is currently untreatable. In this project, we plan to define the roles of muscle and motor neuron terminals in the pathogenesis of SMA and to explore the therapeutic mechanism of histone deacetylase inhibitors. These studies will provide important insights about what tissue and molecules are necessary to target therapeutically in SMA and will therefore guide future efforts to develop treatment for this disease.